Implement Community Based Standards of Care

OBJECTIVE
To briefly review steps that should be followed in the progression from considering therapeutic options on the basis of evidence-based medicine (EBM) to implementing formulary decisions and clinical guidelines.


SUMMARY
Results from EBM should guide selection of therapy for routine clinical practice. Pharmacists must spend considerable time carefully reviewing the designs and results of clinical trials and postmarketing information to develop accurate safety and efficacy profiles. The Pharmacy & Therapeutics (P&T) committee also requires pharmacoeconomic data for its deliberations, and that should include information about the economic, clinical, and humanistic value of new therapies. The P&T committee ultimately determines the business value of the new therapy based on the efficacy and safety profile derived from EBM, comparison with treatment alternatives, cost, provider needs, and system orientation.


CONCLUSION
Proper accomplishment of all of these steps should result in adoption of efficacious, safe, and cost-effective therapies.

T here is general agreement that results from well-controlled clinical trials should guide selection of therapy for routine clinical practice. Evidence-based medicine (EBM) has emerged as a paradigm for the practice and teaching of clinical medicine, and it focuses on procurement and interpretation of clinical research in order to choose the most efficacious diagnostic procedures and therapies. 1 This approach to selection of therapy has been driven by both the need to cope with information overload and the requirement to control the cost of therapy. 2 Many considerations must be taken into account when translating EBM into formulary and clinical guidelines. The aim of this paper is to briefly review the steps that should be followed in the progression from consideration of therapeutic options on the basis of EBM to formulary decisions and implementation of clinical guidelines. This review carefully considers each of these steps and their components, providing specific examples of this progression.

EBM is aimed at determining the clinical value of a given therapy. Clinical value is the primary determinant of whether a given drug should be included in a formulary and/or recommended in a clinical guideline.
A number of different features must be considered together in determining the clinical value of a given therapy. These include the product profile, its prescribing information (i.e., U.S. Food and Drug Administration-approved labeling), clinical trial data that is peer reviewed and published, dosage and route of administration, mechanism of action, the prevalence and epidemiology of the clinical condition it is used to treat, the clinical manifestations of that disease, and both clinical and postmarketing data documenting clinical efficacy and safety.

II Pharmacoeconomic Considerations
The second step in the progression from clinical evidence to formulary and clinical guidelines is pharmacoeconomic analysis. This can be accomplished using a variety of models. The discipline of pharmacoeconomics can be defined as the science of measuring the costs and outcomes associated with the use of pharmaceuticals in health care delivery to a patient population. The main purpose of pharmacoeconomic evaluation is to compare the costs and consequences of therapeutic alternatives. There are 4 main types of pharmacoeconomic evaluations: cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), cost-minimization analysis (CMA), and cost-utility analysis (CUA). All of these methods compare treatment alternatives, often a new therapy versus the current standard of care. 3,4 It is important to note that pharmacoeconomic analysis is a step that plans may consider in this process and is not, in itself, a sole determinant of formulary or clinical positioning.
In CBA, both costs and benefits of a treatment are measured in monetary values, with future costs and benefits discounted to their current value. Although this is considered the best approach to economic analysis, its application in pharmacoeconomics and general health care is limited because of difficulties in assigning a monetary value to health outcomes and the life of a patient. 4 CEA compares therapeutic alternatives with different efficacy and safety profiles. Costs are calculated in monetary value and outcomes are determined as clinical values (e.g., decline in blood pressure for an antihypertensive agent or number of cases cured for an antibiotic). In lifetime CEA, outcomes are measured as years of life gained with the new treatment versus the current standard of care. 4 CMA is employed to determine the least expensive treatment among alternatives with presumably equivalent efficacy and safety profiles. CMA should contain elements necessary to factor the costs of care other than the direct cost of the unit prescription product. 4 In CUA, cost is measured in dollars and outcomes are measured in "quality-adjusted life-years" (QALYs) gained. This measure of treatment utility incorporates both quantity and quality of life. 5 The use of QALYs to define outcomes permits comparison among cost-utility ratios from different pharmacoeconomic analyses. The least-costly treatment alternative is that with the lowest cost per QALY. 4

II Formulary and Clinical Guidelines
The purpose of formulary and clinical guidelines is to optimize patient care. Formularies and guidelines should undergo a process of continual reevaluation in order to improve the overall quality of care. Establishment and updating of formulary and clinical guidelines requires close collaboration among health care professionals, attention to national guidelines, evidence-based assessment of treatment alternatives, and authoritative endorsement based on both peer review and the deliberations of Pharmacy & Therapeutics (P&T) committees.
Pharmacists coordinate P&T committee activities with a priority on clinical value. They may take several approaches to incorporating pharmacoeconomics into formulary decisions. Published pharmacoeconomic studies from the primary literature may be extracted and evaluated, and many approaches have been proposed for the critical evaluation of pharmacoeconomic literature. 4,6 If there are no pharmacoeconomic studies available, the P&T committee may decide to perform an analysis using published data from randomized, controlled studies of efficacy and safety. A cost-effectiveness ratio can be determined by computing all relevant costs for each alternative under consideration.
Many hospitals and health care organizations have treatment guidelines for the management of specific diseases. Pharmacists are often involved in guideline development. This process begins with a comparison of the efficacy and safety profiles of available treatments based on results from clinical trials. The multidisciplinary process involves physicians, pharmacists, and administrators and may also require pharmacoeconomic evaluation. 4 Pharmacoeconomic studies may guide clinicians in making cost-effective choices for specific categories of patients, but these choices may not be the most cost effective for each individual patient. Pharmacoeconomic analysis is designed to evaluate the costs and benefits of different therapies that will be delivered to large numbers of patients with clearly defined characteristics. In practice, patient-specific factors (e.g., drug allergies, comorbid conditions) can make the most cost-effective agent a very individual choice. 4,7 Physicians and pharmacists need to carefully assess individual patient factors as well as population-based analysis in order to effectively translate principles derived from pharmacoeconomics to actual clinical practice. 4

II Clinical Guidelines
In many hospitals and institutions, local treatment guidelines are implemented for specific disease states. Pharmacists are often involved in developing treatment guidelines, policies, and protocols. As in formulary inclusion, the process of establishing guidelines starts from the evaluation of the available treatments and comparison of efficacy and safety profiles derived from clinical trials data. The aim is to provide the correct therapy for each patient and to deliver that intervention at the appropriate time. The development of clinical guidelines requires consideration of diagnostic, treatment, drug utilization, and reauthorization criteria, if applicable. Diagnostic criteria identify indications that constitute acceptable uses for a formulary drug. The P&T committee should establish any protocols restricting use to specific diagnoses and conditions. Treatment criteria identify approved drugs for use in specific labeled indications as well as total episodes of care based on sound principles. Drug utilization criteria identify approved frequency and/or length of product administration, sequencing of utilization, and duration of therapy.

II Case Studies
This section includes 2 case studies designed to illustrate application of the principles considered in the preceding sections. The first involves the use of 3-hydroxy-3 methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) to treat hypercholesterolemia and reduce the risk for cardiovascular events in primary and secondary prevention. The second study deals with the use of new highly targeted biologic agents to treat patients with psoriasis.

Treatment of Hypercholesterolemia
There is strong evidence linking hypercholesterolemia to increased risk for cardiovascular disease, and many studies have shown that statin therapy significantly reduces levels of plasma cholesterol, particularly low-density lipoprotein cholesterol (LDL-C), and also lowers the risk for cardiovascular events in both primary and secondary prevention.

Primary Prevention Data from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) indicated that lovastatin treatment reduced the risk of major coronary events by 37% in
Implementing Community-Based Standards of Care 6,505 men and women without documented coronary heart disease (CHD) who were followed for an average of 5.2 years. 8 Similarly, results from the West of Scotland Coronary Prevention Study (WOSCOPS), which included 6,595 men with no history of myocardial infarction (MI) who had elevated total cholesterol levels, showed that treatment with pravastatin decreased the risk of CHD-related death by 33%. 9

Secondary Prevention
Results from several trials have also demonstrated the ability of statin therapy to decrease the risk of cardiovascular events in patients with documented CHD. Findings from the Cholesterol and Recurrent Events (CARE) trial, which included 3,583 men and 576 women with a history of MI and elevated total cholesterol and LDL-C, indicated that treatment with pravastatin reduced CHD-related mortality by 24%. 10 Results from the Scandinavian Simvastatin Survival Study (4S), a trial that included 4,444 patients with angina pectoris or previous MI and elevated total cholesterol, showed that the relative risk for CHD death was reduced by 42% for patients who received simvastatin. 11 Results from the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial, which included 9,014 patients with a history of MI or hospitalization for unstable angina, indicated a 24% reduction in relative risk for CHD-related death among patients who received pravastatin. 12 Yusuf has summarized the relationships between LDL-C and cardiovascular risk from these studies (Figure 1), and the results demonstrate a strong benefit in reducing LDL-C levels as secondary prevention and a smaller benefit in primary prevention. 13 All of these results are consistent with those from more recent clinical trials that have demonstrated the effectiveness of statin therapy in patients with acute coronary syndromes. 14,15

The Guidelines The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) focuses on reducing LDL-C levels as the primary goal of lipid-lowering therapy. Target LDL-C levels differ according to a patient' s 10-year CHD risk (Table 1). A goal of <100 mg/dL is suggested for patients with CHD or its risk equivalents (other clinical forms of atherosclerotic disease or diabetes that confer a >20% chance of CHD within 10 years, according to the Framingham scoring system). Individuals without CHD but with
≥2 risk factors (cigarette smoking, hypertension, high-density lipoprotein cholesterol [HDL-C] <40 mg/dL, family history of premature CHD, age ≥45 years for men and ≥55 years for women) should aim for an LDL-C <130 mg/dL. The goal for individuals without CHD and <2 risk factors is <160 mg/dL. 16 A very recent update of these guidelines advocates even more aggressive treatment of hypercholesterolemia, particularly in high-risk patients. It is now suggested that the target for LDL-C should be <70 mg/dL in patients at very high risk for cardiovascular events. 17

Trials: AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; CARE = Cholesterol and Recurrent Events; LIPID = Long-Term Intervention with Pravastatin in Ischaemic Disease; WOSCOPS = West of Scotland Coronary Prevention Study; 4S = Scandinavian Simvastatin Survival Study.
NCEP ATP III Goals for LDL-C 16

Pharmacoeconomics
Aggressive implementation of the NCEP ATP III guidelines, according to current estimates, would result in more than 36 million Americans being considered eligible for lipid modification via drug therapy. 18 Unlimited use of LDL-C lowering drugs, although potentially clinically effective in reducing CHD risk, would be costly, and limited resources must be targeted to provide the greatest health benefits. Economic analysis facilitates patient selection to maximize incremental benefits relative to incremental costs.
Formal economic analysis of the most recent clinical trials with statins suggests that secondary prevention of CHD is very cost effective in comparison with existing treatment and prevention strategies. Primary prevention is also cost effective to a lesser degree and has a much wider range of cost-effectiveness depending on individual baseline risk. Cost-effectiveness can be better maximized in primary prevention by treating patients at the highest absolute risk of CHD (Table 2). 19

Use of Biologic Agents to Treat Psoriasis
Psoriasis is one of the more common forms of chronic dermatitis in the world. This disease affects about 6 million people in the United States alone and has marked negative physical and psychological impacts on patients. 20 The overall cost of treating patients with clinically significant disease has been estimated to be $649.6 million each year. 21 Until recently, no systemic therapies were suitable for long-term treatment of psoriasis because of the high risk for toxicity. 22 It is now understood that T-cells and the cytokines they secrete play central roles in the pathogenesis of psoriasis, and new targeted biologic agents have been developed for treatment of this disease. 22 A consensus statement from the American Academy of Dermatology recommends that biologic agents may be considered among the first-line treatment options in patients who are candidates for systemic therapy and that such treatment may be appropriate for patients with psoriasis on the palms and soles, head and neck, or genitalia, or when the disease involves >5% of the skin surface. 23 Three new agents that have been used effectively for the treatment of psoriasis are alefacept, efalizumab, and etanercept (Table 3). [24][25][26] Alefacept is a fully humanized LFA-3/IgG1 that binds to CD2 and thus prevents the activation of T-cells. Clinical trial results have demonstrated that alefacept provides responses that are sustained for up to 18 months in patients with psoriasis. 27 Efalizumab is a recombinant humanized IgG1 that binds to CD11a, inhibiting the binding of T-cells to other cells as well as T-cell activation. This monoclonal antibody has also been shown to be effective for the treatment of patients with psoriasis. 25,28 Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kD (p75) tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgG1. Etanercept binds specifically to TNF and blocks its interaction with cell surface TNF receptors. The naturally occurring TNF cytokine is involved in normal inflammatory and immune responses, and plays an important role in a wide range of inflammatory immune system diseases, including rheumatoid arthritis (RA), polyarticular-course juvenile rheumatoid arthritis (JRA), ankylosing spondylitis (AS), and psoriasis. 24 Etanercept has been shown to be highly effective for treatment of patients with psoriasis. 29 While all of these new agents are effective for the treatment of patients with psoriasis, they do differ in a number of parameters (  the percentage of patients in which they are effective, requirements for hematologic monitoring, likelihood of rebound when treatment is interrupted, and range of indications and, thus, potential for use in patients with psoriasis and other comorbid autoimmune disease. [24][25][26] P&T committees must consider a number of issues with respect to these potent new therapies. First, unlike the statins, there are substantial differences among these agents with respect to route of administration and monitoring requirements. This can make a given agent more or less useful for patients who cannot easily visit the hospital or clinic on a regular basis. There are also differences in their potential for use in patients with psoriasis and other comorbid autoimmune disease. Etanercept is also approved for use in patients with RA, psoriatic arthritis, and AS. 24 These new biologic therapies are similar in that they are not appropriate for patients with mild psoriasis. However, they do appear to have an advantage over other treatment approaches for patients with severe disease who have failed nonsystemic treatments. These new biologic agents should be considered as first-line treatment options, but only in patients in whom other therapies have failed and where at least 5% of the body surface is affected by the disease.

II Conclusions
The process of developing formulary and clinical guidelines includes several important steps that require considerable effort on the part of the pharmacists to prepare information for evaluation by P&T committees. Determination of the clinical value of new therapies is achieved by using the tools of EBM, and pharmacists must carefully review clinical trials and may also require pharmacoeconomic data for their deliberations; such data should include information about the economic, clinical, and humanistic value of new therapies. P&T committees ultimately determine the business value of each new therapy, and that determination is based on the efficacy and safety profile derived from EBM, comparison with treatment alternatives, cost, provider needs, and system orientation. Accomplishment of all of these steps should result in adoption of efficacious, safe, and cost-effective therapies and treatment guidelines for our patients.